TY - JOUR T1 - Factors for differential outcome across cancers in clinical molecular-targeted fluorescence imaging JF - Journal of Nuclear Medicine JO - J Nucl Med DO - 10.2967/jnumed.121.263674 SP - jnumed.121.263674 AU - Quan Zhou AU - Nynke S. van den Berg AU - Wenying Kang AU - Jacqueline Pei AU - Naoki Nishio AU - Stan van Keulen AU - Myrthe A. Engelen AU - Yu-Jin Lee AU - Marisa Hom AU - Johana C. M. Vega Leonel AU - Zachary Hart AU - Hannes Vogel AU - Romain Cayrol AU - Brock A. Martin AU - Mark Roesner AU - Glenn Shields AU - Natalie Lui AU - Melanie Hayden Gephart AU - Roan C. Raymundo AU - Grace Yi AU - Monica Granucci AU - Gerald A. Grant AU - Gordon Li AU - Eben L. Rosenthal Y1 - 2022/03/01 UR - http://jnm.snmjournals.org/content/early/2022/03/24/jnumed.121.263674.abstract N2 - Clinical imaging performance using a fluorescent antibody was compared across three cancers to elucidate physical and biological factors contributing to differential translation of epidermal growth factor receptor (EGFR) expression to macroscopic fluorescence in tumors. Methods: Thirty-one patients with high-grade glioma (HGG, n = 5), head-and-neck squamous cell carcinoma (HNSCC, n = 23) or lung adenocarcinoma (LAC, n = 3) were systemically infused with 50 mg panitumumab-IRDye800, 1 – 3 days prior to surgery. Intraoperative open-field fluorescent images of the surgical field were acquired, where imaging device settings and operating room lighting conditions were tested on tissue-mimicking phantoms. Fluorescence contrast and margin size were measured on resected specimen surface. Antibody distribution and EGFR immunoreactivity were characterized in macroscopic and microscopic histological structures. Integrity of the blood-brain barrier (BBB) was examined via tight junction protein (claudin-5) expression with immunohistochemistry. Stepwise multivariate linear regression of biological variables was performed to identify independent predictors of panitumumab-IRDye800 concentration in tissue. Results: Optimally acquired at the lowest gain for tumor detection with ambient light, intraoperative fluorescence imaging enhanced tissue-size dependent tumor contrast by 5.2-fold, 3.4-fold and 1.4-fold in HGG, HNSCC and LAC, respectively. Tissue surface fluorescence target-to-background ratio correlated with margin size and identified 78 – 97% of at-risk resection margins ex vivo. In 4 µm-thick tissue sections, fluorescence detected tumor with 0.85 – 0.89 areas under the receiver operating characteristic curves. Preferential breakdown of BBB in HGG improved tumor specificity of intratumoral antibody distribution relative to that of EGFR (96% vs 80%) despite its reduced concentration (3.9 ng/mg tissue) compared to HNSCC (8.1 ng/mg) and LAC (6.3 ng/mg). Cellular EGFR expression, tumor cell density, plasma antibody concentration and delivery barrier were independently associated with local intratumoral panitumumab-IRDye800 concentration with 0.62 goodness-of-fit of prediction. Conclusion: In multi-cancer clinical imaging of receptor-ligand based molecular probe, plasma antibody concentration, delivery barrier, as well as intratumoral EGFR expression driven by cellular biomarker expression and tumor cell density, led to heterogeneous intratumoral antibody accumulation and spatial distribution while tumor size, resection margin, and intraoperative imaging settings substantially influenced macroscopic tumor contrast. ER -